AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease
Authors: Mary E. Rinella, Brent A. Neuschwander-Tetri, Mohammad Shadab Siddiqui, Manal F. Abdelmalek, Stephen Caldwell, Diana Barb, David E. Kleiner, Rohit Loomba
Journal: Hepatology (2023)

PREAMBLE The study of NAFLD has intensified significantly, with more than 1400 publications since 2018, when the last American Association for the Study of Liver Diseases (AASLD) Guidance document was published.1 This new AASLD Guidance document reflects many advances in the field pertinent to any practitioner caring for patients with NAFLD and emphasizes advances in noninvasive risk stratification and therapeutics. A separate guideline focused on the management of patients with NAFLD in the context of diabetes has been written jointly by the American Association of Clinical Endocrinology and AASLD.2 Given the significant growth in pediatric NAFLD, it will not be covered here to allow for a more robust discussion of the diagnosis and management of pediatric NAFLD in the upcoming AASLD Pediatric NAFLD Guidance. A "Guidance" differs from a "Guideline" in that it is not bound by the Grading of Recommendations, Assessment Development and Evaluation system. Thus, actionable statements rather than formal recommendations are provided herein. The highest available level of evidence was used to develop these statements, and, where high-level evidence was not available, expert opinion was used to develop guidance statements to inform clinical practice. Key points highlight important concepts relevant to understanding the disease and its management. The most profound advances in NAFLD relevant to clinical practice are in biomarkers and therapeutics. Biomarkers and noninvasive tests (NITs) can be used clinically to either exclude advanced diseases or identify those with a high probability of cirrhosis.3,4 NIT "cut points" vary with the populations studied, underlying disease severity, and clinical setting. Those proposed in this guidance are meant to aid decision-making in the clinic and are not meant to be interpreted in isolation. Identifying patients with "at-risk" NASH (biopsy-proven NASH with stage 2 or higher fibrosis) is a more recent area of interest. Although the definitive diagnosis and staging of NASH remain linked to histology, noninvasive tools can now be used to assess the likelihood of significant fibrosis, predict risk of disease progression and decompensation, make management decisions, and, to some degree, assess response to treatment. There is an ongoing debate over the nomenclature of fatty liver disease, which had not been finalized at the time this guidance was published. At the culmination of a rigorous consensus process, it is intended that any formal change in nomenclature will advance the field without a negative impact on disease awareness, clinical trial endpoints, or the drug development/approval process. Furthermore, it should allow for the emergence of newly recognized disease subtypes to address the impact of disease heterogeneity, including the role of alcohol, on disease progression and response to therapy. Input from patients has been central to all stages of the consensus process to ensure the minimization of nomenclature-related stigma. DEFINITIONS NAFLD is an overarching term that includes all disease grades and stages and refers to a population in which ≥5% of hepatocytes display macrovesicular steatosis in the absence of a readily identified alternative cause of steatosis (eg, medications, starvation, monogenic disorders) in individuals who drink little or no alcohol (defined as < 20 g/d for women and <30 g/d for men). The spectrum of disease includes NAFL, characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation, and NASH, which is additionally characterized by the presence of inflammation and cellular injury (ballooning), with or without fibrosis, and finally cirrhosis, which is characterized by bands of fibrous septa leading to the formation of cirrhotic nodules, in which the earlier features of NASH may no longer be fully appreciated on a liver biopsy. UPDATE ON EPIDEMIOLOGY AND NATURAL HISTORY The prevalence of NAFLD and NASH is rising worldwide in parallel with increases in the prevalence of obesity and metabolic comorbid disease (insulin resistance, dyslipidemia, central obesity, and hypertension).5,6 The prevalence of NAFLD in adults is estimated to be 25%–30% in the general population7–9 and varies with the clinical setting, race/ethnicity, and geographic region studied but often remains undiagnosed.10–14 The associated economic burden attributable to NASH is substantial.15–17 The prevalence of NASH in the general population is challenging to determine with certainty; however, NASH was identified in 14% of asymptomatic patients undergoing colon cancer screening.14 This study also highlights that since the publication of a prior prospective prevalence study,18 the prevalence of clinically significant fibrosis (stage 2 or higher fibrosis) has increased >2-fold. This is supported by the projected rise in NAFLD prevalence by 2030, when patients with advanced hepatic fibrosis, defined as bridging fibrosis (F3) or compensated cirrhosis (F4), will increase disproportionately, mirroring the projected doubling of NASH.5,19 As such, the incidence of hepatic decompensation, HCC, and death related to NASH cirrhosis are likewise expected to increase 2- to 3-fold by 2030.5 Although expected to increase further, NASH-related cirrhosis is already the leading indication for liver transplantation in women and those >65 years of age and is on par with alcohol as the leading indication overall.20–22 Natural history of disease progression Data from meta-analyses and pooled studies demonstrate that fibrosis and the presence of steatohepatitis are the primary predictors of disease progression.23–25 The collinearity between NASH and the fibrosis it induces makes it challenging to demonstrate the independent contribution of NASH to fibrosis and adverse outcomes in multivariable analyses.26,27 Although fibrosis is the primary determinant of adverse outcomes, increased liver-related morbidity and mortality and nonhepatic malignancy are observed in patients with NAFLD even in the absence of fibrosis on initial biopsy.25 Nevertheless, patients with NASH and at least stage 2 fibrosis (F2), referred to as "at-risk" NASH, have a demonstrably higher risk of liver-related morbidity and mortality.24,28 Fibrosis progression is influenced by many factors such as the presence and severity of comorbid disease, genomic profile, and environmental factors. A meta-analysis of placebo-treated patients in 35 NASH trials found minimal progression, suggesting that nonpharmacologic factors (frequent visits/monitoring, dietary or lifestyle counseling, or changes) may reduce progression.29 An earlier meta-analysis of cohorts with longitudinal paired biopsies30 demonstrated a NAFLD fibrosis progression rate of one stage per 7 years in those with NASH versus 14 years for those with NAFL.30 The diagnosis of cirrhosis, determined by biopsy or noninvasively, is important because it changes clinical management. Those with cirrhosis require biannual screening for HCC as well as screening for varices and monitoring for signs or symptoms of decompensation.31,32 Among patients with cirrhosis, progression to clinical decompensation ranges from 3% to 20% per year.12,33–35 Association between disease stage and adverse outcomes The most common causes of death in patients with NAFLD overall are cardiovascular disease (CVD) and nonhepatic malignancy, followed by liver disease. The amount of liver fibrosis identified histologically in patients with NAFLD has been strongly linked to the development of liver-related outcomes and death.24,26,36,37 Bridging fibrosis and cirrhosis are associated with an exponentially greater risk of liver-related morbidity and mortality than earlier stages of fibrosis.23,24,35 In a prospective study of 1773 patients, all-cause mortality in those with fibrosis stages 0–2 was 0.32 per 100 person-years, compared with 0.89 per 100 person-years in those with bridging fibrosis and 1.76 per 100 person-years in those with cirrhosis. After correcting for multiple factors, hepatic decompensation was associated with all-cause mortality (HR, 6.8; 95% CI, 2.2–21.3).35 Cirrhosis regression has been associated with a 6-fold reduction in liver-related events in clinical trials.38Key points: Patients with NASH and F2–4 fibrosis are at higher risk for liver-related events and mortality and are considered to have "at-risk" NASH. The rates of fibrosis progression and hepatic decompensation vary depending on baseline disease severity, genetic, individual environmental, and comorbid disease determinants. CVD and nonhepatic malignancies are the most common causes of mortality in patients with NAFLD without advanced fibrosis; death from liver disease predominates in patients with advanced fibrosis. MOLECULAR AND CELLULAR PATHOGENESIS The presence and severity of NAFL and NASH are substantially determined by factors that govern the supply and disposition of fatty acids, diacylglycerols, ceramides, cholesterol, phospholipids, and other intrahepatic lipids. Energy oversupply and limited adipose tissue expansion contribute to insulin resistance and metabolic disease.39 When energy intake exceeds metabolic needs and disposal capacity, carbohydrates, in the form of dietary sugars (eg, fructose, sucrose, and glucose), drive the formation and accumulation of intrahepatic fat from de novo lipogenesis (DNL).40,41 There is substantial interindividual heterogeneity in the role of DNL among patients with NAFLD.42,43 In addition, the type of fat consumed plays a role in the development of NASH, with a higher risk associated with saturated versus unsaturated fat consumption (Figure 1).44–46FIGURE 1: Pathogenic drivers of NAFLD as therapeutic targets. Overview of the major mechanisms that lead to the phenotype of NASH and its consequences, many of which can be leveraged therapeutically. Not shown are the many areas where genetic polymorphisms may play a role and where important modifying factors such as cholesterol, types of dietary fats consumed [saturated vs. polyunsaturated fatty acid (PUFA)], the gut microbiome, uric acid, and periodic hypoxia (sleep apnea) may also influence these pathways. A primary disease driver may be an oversupply of fat to adipocytes such that their ability to store triglyceride without inducing cell stress is exceeded, which activates inflammatory pathways and causes insulin resistance. Understanding the major drivers of NASH facilitates the rational development of therapies for patients with NASH. Specific sites of intervention that might prevent or resolve NASH include interventions that modulate food intake (eg, portion sizes, bariatric surgery, satiety regulators), increase energy disposal (eg, exercise, thermogenesis), improve adipocyte insulin sensitivity [eg, peroxisome proliferator-activated receptor (PPAR)γ ligands], impair de novo lipogenesis (eg, acetyl-coenzyme A carboxylase and fatty acid synthase inhibitors), increase hepatic oxidative metabolism (PPARα ligands and thyroid hormone receptor beta agonists), and attenuate inflammation, cell death, and fibrogenesis. Therapeutic agents affecting multiple metabolic pathways throughout the body with potential beneficial effects on the liver include peptide hormone analogs (eg, analogs of fibroblast growth factor-19, fibroblast growth factor-21, glucagon-like peptide-1, gastric inhibitory peptide, glucagon) and nuclear receptor ligands such as drugs that target PPARα, PPARδ, PPARγ, thyroid hormone receptor β, and farnesoid X receptor. Abbreviations: ER, endoplasmic reticulum; CVD, cardiovascular disease.Insulin resistance is nearly universal in patients with NAFLD and is present in the liver, adipose tissue, and muscle.47 Adipose tissue insulin resistance is characterized by increased release of free fatty acids from adipocytes (lipolysis) in the fasting state48 and worsens with the progression of NAFLD to NASH.39,47,49 Important factors that govern energy disposal include the frequency and intensity of exercise, the activation of brown adipose tissue to an energy-consuming thermogenic phenotype, and counterregulatory mechanisms that diminish energy disposal in response to reductions in calorie intake.39,50 The ability and desire to engage in regular exercise can be strongly influenced by personal, community, corporate, societal, and legislative decisions, all of which thus have roles in the development of NASH. The heterogeneity of factors contributing to the pathophysiology of NASH among patients has impeded the development of diagnostic tests and therapeutics.51 Although in some patients, the development and progression of NASH are driven by substrate overload and insulin resistance, in other patients, disease progression is heavily influenced by genetic factors impacting hepatocyte lipid handling.43 Genetic polymorphisms have been associated with more advanced liver disease and the development of HCC in NASH. The I148M polymorphism of PNPLA3 impairs lipolysis of triglyceride in lipid droplets,52 and polymorphisms in other proteins that play a role in hepatocyte fat metabolism have also been linked to the prevalence and severity of NAFLD, including transmembrane 6 superfamily member 2 (TM6SF2), which may play a role in cholesterol metabolism,53 and MBOAT7, which influences phospholipid metabolism.54 Recently, loss-of-function variants in HSD17B13, a gene that encodes an enzyme that also localizes to lipid droplets in hepatocytes, have been linked to protection against NASH, progressive fibrosis, and HCC.55 Rare loss-of-function mutations in CIDEB, a protein needed for activation of DNL,56 have also been shown to be protective.57 A host of additional factors, the review of which is beyond the scope of this guidance, contribute to heterogeneity in disease activity and progression.49,58–63 Additional factors such as hepatocyte uric acid production, exposure to products derived from the gut microbiome, and perhaps low hepatic magnesium levels, may also contribute to the NASH phenotype.64–69 Transcriptomic profiling of large cohorts of patients is further contributing to our understanding of this disease heterogeneity and its progression.70,71 The response of the liver to lipotoxic injury includes activation and recruitment of resident macrophages, which further contributes to hepatocellular injury and stellate cell activation as part of a complex interplay among hepatic cell types.60,72,73 Although markers of oxidative stress have been a consistent finding in NASH, its role in the pathogenesis of NASH in humans remains uncertain.74Key points: Fundamental elements of NASH pathogenesis include an imbalance between nutrient delivery to the liver and their utilization and disposal coupled with adipose tissue dysfunction. Interindividual differences in genetic, dietary, behavioral, and environmental factors influence disease course. Systemic inflammation, particularly stemming from dysfunctional adipose tissue, contributes to disease progression. Insulin resistance contributes to the development of NAFLD and promotes disease progression. COMORBID CONDITIONS ASSOCIATED WITH NAFLD NAFLD is closely linked to and often precedes the development of metabolic abnormalities (insulin resistance, dyslipidemia, central obesity, and hypertension).47,61,75–77 Having several metabolic abnormalities confers an even greater risk of histological progression of NASH and all-cause mortality.8,47,78–81 The association between NAFLD and metabolic comorbidities may also reflect bidirectional interactions between the liver and other endocrine organs (eg, pancreas, adipose tissue, muscle) through the secretion of hepatokines that regulate fatty acid metabolism, insulin action, and glucose metabolism,82–88 adipokines, and myokines.39,89,90 Obesity The presence and severity of obesity are associated with NAFLD and disease progression.91–93 Body fat distribution is an important determinant of the contributory role of obesity in NAFLD (Table 1). Android body fat distribution, characterized by increased truncal subcutaneous fat and visceral fat confers a higher risk of insulin resistance, CVD, and hepatic fibrosis, irrespective of body mass index (BMI).94–99 In contrast, gynoid body fat distribution, characterized by increased subcutaneous body fat predominantly in the hips or buttocks, appears to be protective against NAFLD.39,100 Visceral fat, which is more metabolically active and inflammatory than subcutaneous fat, mediates the majority of this risk.101–105 As adipose tissue becomes more metabolically stressed, dysfunctional, and inflamed, insulin signaling is progressively impaired, promoting the inappropriate release of fatty acids leading to intrahepatic lipid accumulation and inflammation.47,106,107 TABLE 1 - Initial evaluation of a patient with NAFLD History Weight history; medical comorbidities; recent and current medications; family history of T2DM, NAFLD, or cirrhosis; screening for OSA; alcohol use, including amount, pattern of use, and duration Physical examination Body fat distribution (eg, android vs. gynoid, lipodystrophic), features of insulin resistance (eg, dorsal-cervical fat pad, acanthosis nigricans), features of advanced liver disease (eg, firm liver, splenomegaly, prominent abdominal veins, ascites, gynecomastia, spider angiomata, palmar erythema) Laboratory tests Hepatic panel, CBC with platelets, fasting plasma glucose and glycated hemoglobin (A1c), fasting lipid profile, creatinine and urine microalbumin or protein to creatinine ratio, hepatitis C if not previously screened. Consider as appropriate other causes of steatosis/steatohepatitis (). Additional evaluation if elevated liver chemistries present: autoimmune serologies, transferrin saturation, ceruloplasmin, alpha-1 antitrypsin genotype, or phenotype Abbreviations: CBC, complete blood count; OSA, obstructive sleep apnea; T2DM, type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) T2DM is the most impactful risk factor for the development of NAFLD, fibrosis progression, and HCC.108–111 Given the central pathogenic role that insulin resistance plays in the pathogenesis of both T2DM and NAFLD, it is not surprising that patients with T2DM have a higher prevalence of NAFLD (ranging from 30% to 75%)10,112,113 and a higher risk of developing NASH with fibrosis.93,114–117 Furthermore, the probability of advanced fibrosis increases with the duration of T2DM. Although there is potential for lead time and length time biases, these studies underscore the strong relationship between T2DM and NAFLD. The relationship between NAFLD and T2DM is bidirectional in epidemiological studies. Early in its course, NAFLD is associated with a reduction in insulin sensitivity,47 even in the absence of overt diabetes. The presence of NAFLD is associated with a 2- to 5-fold risk of incident diabetes,75,118–121 and therefore, patients with NAFLD should be screened for the presence of T2DM (Table 1). Furthermore, as liver disease progresses, so does insulin resistance and beta cell failure, making diabetes more challenging to manage.107 The role of glycemic control in the progression of NAFLD/NASH remains controversial, with 2 small studies showing an association between poor glycemic control and hepatocellular injury and liver fibrosis,68,122 whereas other studies have not corroborated this finding.116,117,123 Although NAFLD has also been described in patients with type 1 diabetes, its prevalence is much lower than in T2DM, and it is closely related to coexistent metabolic risk factors (eg, higher BMI).124,125 Hypertension Hypertension is commonly associated with NAFLD. There is a higher incidence of hypertension in those with NAFLD across the disease spectrum, with incidence rates of 6.5 per 100 person-years in early disease to 14.5 per 100 person-years in those with cirrhosis.35 The presence of hypertension is clearly additive to other metabolic comorbidities with respect to the epidemiological risk of NASH126,127 and has been associated with fibrosis progression.30 Whether hypertension mechanistically promotes the development of NAFLD/NASH or the inverse, or both are manifestations of underlying metabolic disease drivers, has not been established.128,129 Dyslipidemia Patients with NAFLD are twice as likely to exhibit plasma lipid abnormalities as those without NAFLD,120 and the serum lipid subfractions are more atherogenic in patients with NAFLD.130,131 NASH resolution can lead to improved plasma HDL cholesterol and triglyceride levels and favorably impact lipoprotein subfractions, although it is unclear to what extent this is driven by the mechanism of the therapeutic intervention.132–134 As patients progress to cirrhosis, they continue to remain at high risk for coronary artery disease135 despite the normalization of serum lipids and lipoproteins due to hepatic synthetic failure.130,136 Management of dyslipidemia in NAFLD should include the use of moderate-intensity to high-intensity statins as first-line therapy based on lipid risk levels and atherosclerotic CVD risk scores. Combination therapies of statins with other hypolipemic agents, such as ezetimibe, PCSK-9 inhibitors, inclisiran, bempedoic acid, fibrates, omega 3 fatty acids, or icosapent ethyl, should be considered when monotherapy with a statin does not achieve therapeutic goals. Statins are safe in patients with NAFLD across the disease spectrum, including advanced liver disease, and lead to a demonstrable reduction in cardiovascular morbidity and mortality.137–140 However, in clinical practice, they are often underused despite extensive data demonstrating safety, even among patients with cirrhosis.141–144 Statins are also considered safe in the context of compensated cirrhosis and may have beneficial effects on future decompensation and HCC risk, although additional confirmatory data are needed.138 Although statins have been safely used in patients with decompensated cirrhosis, the risk of statin-induced adverse events might be higher in this population,144 and thus more caution is warranted. In patients with decompensated cirrhosis and high CVD risk undergoing evaluation for liver transplantation, statin use can be considered with careful monitoring.136 In patients with NAFLD and severely elevated triglycerides levels (eg, >500 mg/dL), fibrates, or a combination of fibrates with prescription grade omega-3 fatty acids or icosapent ethyl, should be used to reduce the risk of pancreatitis. Fibrates may also improve atherosclerotic CVD outcomes when triglyceride concentrations are ≥200 mg/dL and HDL-C concentrations are <40 mg/dL. In high-risk individuals, icosapent ethyl is indicated as an adjunct to statin therapy to reduce atherosclerotic CVD risk. Pioglitazone can be considered for optimization of glycemic control due to its concomitant benefits on lipid profile. Caution should be taken when statins are used in combination with fibrates due to a higher risk of statin-induced myopathy. Obstructive sleep apnea (OSA) OSA is associated with NAFLD,145 and several studies suggest OSA is also associated with more advanced NAFLD/NASH histology.146–151 Intermittent hypoxia, a critical consequence of OSA, has been linked to mitochondrial dysfunction,145 dysregulation of glucose and lipid metabolism,152,153 worse insulin resistance,154–156 and increased hepatic DNL.157 Given the strong association between NAFLD and OSA, patients with NAFLD who are overweight or obese should be screened for OSA, and polysomnography or other sleep studies should be considered for those at high risk. CVD CVD is an important cause of death in patients with NAFLD158; however, the extent to which NAFLD independently drives CVD is unclear. A strong association exists between NAFLD and atherosclerotic heart disease, heart failure, and arrhythmias, particularly atrial fibrillation.159–167 Perturbed lipoprotein metabolism, endothelial function, increased presence and higher-risk nature of atherosclerotic lesions, and impaired ischemic compensatory mechanisms support the link between NAFLD and CVD.130,168–170 Furthermore, in a large prospectively studied observational cohort, the incidence of cardiac events was the same across all fibrosis stages; however, the number of cardiac events was relatively low.35 Optimizing the management of CVD risk factors with the goal of reducing CVD morbidity and mortality is critical to improving outcomes in patients with NAFLD.36,171,172 Aggressively treating comorbid conditions such as hypertension, dyslipidemia, and hyperglycemia and promoting smoking cessation is recommended to decrease CVD in those at risk.173 Chronic kidney disease (CKD) A meta-analysis of 20 cross-sectional studies (n=28,000 individuals) found that NAFLD was associated with a 2-fold increased prevalence of CKD.174 NAFLD overall, and NASH specifically, are also associated with microvascular diabetic complications, especially CKD.175,176 Recently published data from the NASH CRN demonstrate a higher prevalence of CKD in patients with advanced fibrosis compared with lower fibrosis stages.35 The extent to which the liver mechanistically contributes to the development of CKD independent of associated metabolic disease remains to be determined.Guidance statements: 1. Statins are safe and recommended for CVD risk reduction in patients with NAFLD across the disease spectrum, including compensated cirrhosis. 2. Limited data exist on the safety and efficacy of statins in patients with decompensated cirrhosis, although statin use with careful monitoring could be considered in patients with high CVD risk. 3. Hypertriglyceridemia can be managed through lifestyle changes and supplementation with omega-3 fatty acids, icosapent ethyl, or fibrates. 4. Patients with diabetes are at higher risk for NASH and advanced fibrosis and should be screened for advanced fibrosis. 5. Patients with NAFLD should be screened for the presence of T2DM. Key points: Prevalence and incidence of CKD is higher among patients with NASH and advanced fibrosis. Death from nonhepatic malignancies is a common cause of death in patients with NAFLD, and thus, adherence to age-appropriate cancer screening has the potential to improve survival. INITIAL EVALUATION OF A PATIENT WITH NAFLD Patients with NAFLD are most commonly referred with incidentally noted hepatic steatosis on imaging or elevated liver chemistries. It is important to note that normal values provided by most laboratories are higher than what should be considered normal in NAFLD, in which a true normal alanine aminotransferase (ALT) ranges from 29 to 33 U/L in men and from 19 to 25 U/L in women.177 Initial evaluation of such patients should include screening for metabolic comorbidities, assessment of alcohol intake, and exclusion of other causes of liver disease as well as physical examination to identify signs of insulin resistance and advanced liver disease (Table 1). When the clinical profile is atypical (eg, not associated with metabolic comorbidities) or accompanied by additional signs or symptoms suggesting additional/alternate etiologies, less common causes of steatosis or steatohepatitis should be excluded (Table 2). Rare causes of steatosis or fibrosing steatohepatitis can present in isolation or explain an exaggerated NASH phenotype and should be considered in specific clinical contexts (Table 2).178 Several drugs can also lead to hepatic steatosis or steatohepatitis or exacerbate disease in those with underlying NAFLD and should be identified during initial evaluation (Table 3). Although gene-based risk stratification is currently not recommended in clinical practice, familial aggregation of insulin resistance and NAFLD supports gene-environment interactions in the risk for NAFLD, NASH, and advanced fibrosis.209,210 TABLE 2 - When to consider testing for less common causes of hepatic steatosis and steatohepatitis Condition Clinical scenario Diagnostic test Treatment Hypobetalipoproteinemia Low LDL, low triglycerides, fat malabsorption ApoB level, genetic testing (MTTP, PCSK-9) Low-fat diet, fat-soluble vitamin supplementation LAL deficiency Markedly elevated LDL-C and low HDL-C, elevated triglycerides, xanthelasma, hypersplenism, advanced fibrosis in young age, predominately microvesicular steatosis on liver biopsy Enzyme assay, genetic testing LAL replacement Nutrient deficiency (eg, carnitine, choline) Anorexia, short bowel, bypass surgeries Nutrient levels Supplementation Wilson disease Younger age, neuropsychiatric symptoms, low alkaline phosphatase, low ceruloplasmin 24-h urine copper; quantitative copper on liver biopsy Chelation Celiac disease Iron deficiency, abdominal pain, bloating, vitamin D deficiency, bone loss, diarrhea, dermatitis herpetiformis Tissue transglutaminase IgA, duodenal biopsy Gluten-free diet Abbreviations: ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; IgA, immunoglobulin A; LAL, lysosomal acid lipase; LDL-C, LDL cholesterol. TABLE 3 - Drugs with potential mechanistic links to macrovesicular steatosis or steatohepatitis Drug Mechanism Histological pattern References Amiodarone Promotion of DNL, impairment of β-oxidation Hepatic steatosis and steatohepatitis, phospholipidosis, cirrhosis 179–184 5-FU Accumulation of 5-FU catabolites reduce hepatic capacity to metabolize lipids Hepatic steatosis 185–188 Irinotecan Induces mitochondrial dysfunction, impaired autophagy Steatohepatitis 189–194 Tamoxifen Estrogen receptor modulator, promotion of DNL, impairment of β-oxidation. *May or may not be independent of concomitant metabolic risk factors Steatosis and steatohepatitis 195–203 Methotrexate Mitochondrial injury (inhibits mitochondrial electron transport chain), injury to canals of Hering Steatosis, steatohepatitis, cirrhosis 204–206 Corticosteroids Exacerbation of metabolic